The Mackall laboratory seeks to develop new immune based therapies for the treatment of pediatric cancer. Specifically, we have focused our efforts primarily on developing immunotherapies that specifically target the small round blue cell sarcomas of childhood. Our work spans mouse models which allow us to develop immune approaches to target metastatic disease and to study Ewings sarcoma biology by applying human tumors to mice, in vitro studies of the interactions between human lymphocytes and sarcoma cells and clinical studies of immunotherapy in patients with sarcomas and neuroblastoma. Major accomplishements from this work include: #1) Demonstration that resistance to TRAIL receptor agonist based killing in Ewings sarcoma is primarily dependent upon diminished caspase-8 expression and demonstration that interferon-gamma potently modulates caspase 8 expression. This work was a collaborative study with our colleagues at the University of Freiburg, Germany (Lissat, et al) and also demonstrated that clinical Ewings sarcoma samples have very heterogeneous caspase-8 expression, thus confirming that agents which can upregulate caspase 8 are likely to be critical for the suggest of TRAIL receptor based therapies in Ewings sarcoma. #2) A second major accomplishment was the initiation of the first clinical trial of anti-TRAIL receptor antibody in pediatric cancers. This is a multicenter study between the NCI Pediatric Oncology Branch, Memorial Sloan Kettering Cancer Center and the University of Cincinnati. We have completed enrollment on two of four dose levels with good safety data thus far and encouraging clinical results. Based upon our preclinical studies, we ultimately hope to combine this agent with interferon in the future and to conduct Phase II studies in appropriate pediatric sarcoma populations. #3) Based upon our previously published results demonstrating that 4-1BB based costimulation can expand Ewing's sarcoma reactive T cells from patients with Ewing's sarcoma, we have produced a master cell bank of artificial antigen presenting cells (aAPCs) expressing 4-1BBL for use in clinical trials of adoptive immunotherapy for ES and potentially other tumors. Early results demonstrate that these artificial antigen presenting cells can induce potent expansion of antigen specific CD8+ cells ex vivo which could then be used for adoptive cellular immunotherapy. (Zhang et al, J of Immunology, 2007, In Press). Future plans are to initiate a clinical trial with these artificial APCs to expand tumor reactive T cells ex vivo prior to their adoptive transfer.